Cranial [radiotherapy]-treated survivors show decreased white matter integrity reflected by significantly decreased [fractional anisotropy] and associated neuropsychological dysfunction 25 years after treatment, although effects of chemotherapy alone seem mild.
—Ilse Schuitema, MSc, and colleagues
Central nervous system–directed chemotherapy and cranial radiotherapy for childhood acute lymphoblastic leukemia or lymphoma have neurotoxic effects. In a study reported in Journal of Clinical Oncology, Ilse Schuitema, MSc, of Leiden University, and colleagues evaluated white matter changes and neuropsychological function in Dutch or Belgian patients 20 to 30 years after receiving chemotherapy or cranial radiotherapy for childhood lymphoid malignancy.1 They found that cranial radiotherapy was associated with decreased white matter integrity (which significantly correlated with age at diagnosis and age at assessment) and poorer neuropsychological function.
In the study, 93 patients treated between 1978 and 1990 at various intensities with (n = 44) and without (n = 49) cranial radiotherapy and 49 healthy controls were assessed with magnetic resonance diffusion tensor imaging and neuropsychological testing. Patients in the cranial radiotherapy group had been treated with radiotherapy at doses ranging from 15 to 30 Gy. Chemotherapy in both the radiotherapy and chemotherapy groups consisted of various regimens of intrathecal or intravenous methotrexate or intrathecal and intravenous methotrexate.
Differences in fractional anisotropy—a diffusion tensor imaging measure of white matter microstructure—were analyzed using whole-brain voxel-based analysis. Neuropsychological function was assessed using the Amsterdam Neuropsychological Tasks program (larger values indicate worse performance) to measure executive function and the short form of the Wechsler Adult Intelligence Scale–Revised to estimate intelligence quotient.
White Matter Integrity and Neuropsychological Performance
Patients who had received cranial radiotherapy had significantly decreased fractional anisotropy (all P < .05) compared with controls in frontal, parietal, and temporal white matter tracts (orbitofrontal white matter, genu, anterior body, and forceps minor of the corpus callosum, cingulum [frontal and parietal], and inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and uncinate fasciculus). Those who had received chemotherapy alone had trends for lower fractional anisotropy in frontal white matter tracts.
Fractional anisotropy values for frontal, parietal, and temporal white matter tracts were significantly correlated with measures of visuomotor control, visuospatial sequencing, and sustained attention work pace (all P < .05). Patients who had received cranial radiotherapy had significantly poorer (all significant on simple contrast vs controls) intelligence quotient (mean, 96.9 vs 107.4; P = .116 for group factor), visuomotor accuracy (3.9 vs 3.3; P = .045 for group factor) and stability (2.6 vs 2.1; P = .052 for group factor), sustained attention work pace (9.5 vs 8.2; P = .005 for group factor), and visuospatial sequencing (8.2 vs 3.2; P < .001 for group factor) compared with controls, whereas those who had received chemotherapy alone had smaller, nonsignificant deficits compared with controls (intelligence quotient, 103.4; visuomotor accuracy, 3.5; visuomotor stability, 2.1; sustained attention work pace, 8.5; visuospatial sequencing, 4.5).
Correlations With Age
Patients who had received cranial radiotherapy had significant positive correlations between fractional anisotropy values and age at diagnosis (corrected for age at assessment) for frontal and parietal white matter and significant negative correlations between fractional anisotropy values and age at assessment (corrected for age at diagnosis, with younger age being worse), for frontal, parietal, and temporal white matter (all P < .05). In control subjects, correlations with age at assessment were not significant. No significant correlations with age at assessment or diagnosis were observed in the chemotherapy group.
Correlations With Dosage
Higher dosage of cranial radiotherapy was associated with significantly worse white matter integrity (P < .05) in mainly frontal, but clusters throughout the brain (including corpus callosum, corona radiata, inferior fronto-occipital fasciculus, and uncinate fasciculus), whereas no interactions or correlations with doses of intravenous or intrathecal methotrexate could be established. No correlations with doses of intravenous or intrathecal methotrexate were found in the chemotherapy group. No effects of doses of cranial radiotherapy or intrathecal or intravenous methotrexate on neuropsychological outcome were found.
The investigators concluded: “Cranial [radiotherapy]-treated survivors show decreased white matter integrity reflected by significantly decreased [fractional anisotropy] and associated neuropsychological dysfunction 25 years after treatment, although effects of chemotherapy alone seem mild. Accelerated aging of the brain and increased risk of early onset dementia are suspected after cranial [radiotherapy], but not after chemotherapy.”
In an accompanying editorial,2 F. Daniel Armstrong, MD, of the University of Miami Miller School of Medicine and Holtz Children’s Hospital, University of Miami/Jackson Memorial Medical Center, commented,
Although the challenges of providing treatment and support to the adult survivors and their families who experience long-term problems associated with long-ago therapy are daunting, there is an opportunity to embark on studies that may bring about changes in treatment and long-term outcomes for the children we are treating today. The potential impact of this late effect in terms of both financial cost and burden to the patient and family is great; a similarly great response from the scientific and funding community is needed. Schuitema et al have issued a wake-up call. The scientific community should not hit the snooze button. ■
Disclosure: The study authors and Dr. Armstrong reported no potential conflicts of interest.
1. Schuitema I, Deprez S, Van Hecke W, et al: Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies. J Clin Oncol. August 19, 2013 (early release online).
2. Armstrong FD: Implications of 25-year follow-up of white matter integrity and neurocognitive function of childhood leukemia survivors: A wake-up call. J Clin Oncol. August 19, 2013 (early release